Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats

McGraw, Matthew D.; Dysart, Marilyn M.; Hendry‐Hofer, Tara B.; Houin, Paul R.; Rioux, Jacqueline S.; Garlick, Rhonda B.; Loader, Joan E.; Smith, R. H.; Paradiso, Danielle; Holmes, Wesley W.; Anderson, Dana R.; White, Carl W.; Veress, Livia A.

doi:10.1165/rcmb.2017-0168oc

Cited by 30 publications

(25 citation statements)

References 46 publications

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“…Furthermore, NM-instillation modified pressure–volume loops, consistent with a restrictive pattern of pulmonary fibrosis. As we previously published, NM-exposure does not affect Newtonian resistance (Rn) and, differently from sulfur mustard exposure, provokes a minimal obstruction of the airways [ 18 , 49 ]. Interestingly, the restrictive pattern observed, appeared at day 10 and was present at least till day 30, suggesting a non-reversible alteration in lung structure following NM exposure.…”

Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Solopov

Biancatelli

Маринова

et al. 2020

IJMS

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Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-β, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Solopov

Biancatelli

Маринова

et al. 2020

IJMS

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“…NM causes injury of both the upper and the lower airways with increased inflammation and increased immunostaining of COX-2, iNOS, and MMP9 [ 17 ]. NM instillation in rats elicits a pro-fibrotic response mediated by the migration of type 2 macrophages [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis

Solopov

Biancatelli

Dimitropoulou

et al. 2021

IJMS

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We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male–female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.

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“…Second, the NM concentrations chosen for exposure were high (>300 mg/m 3 ), as these concentrations are known to cause severe short-and long-term mustard lung morbidity and mortality from previously published in vivo rodent modeling. 6,9,58,59 At such concentrations, the primary cause of acute mortality is airway injury with vascular leak and airway cast formation as supported by our prior in vivo exposures. 9,11,16,60 Lower, noncytotoxic concentrations were not evaluated as lower concentrations are less associated with both acute and chronic morbidity after mustard exposure.…”

Section: Discussionmentioning

confidence: 62%

“…In vitro NM exposure concentrations can be calculated, knowing the volume within the 24‐well culture (3.5 cm 3 ) and assuming all NM evaporated during the 1‐h exposure. Second, the NM concentrations chosen for exposure were high (>300 mg/m 3 ), as these concentrations are known to cause severe short‐ and long‐term mustard lung morbidity and mortality from previously published in vivo rodent modeling 6,9,58,59 . At such concentrations, the primary cause of acute mortality is airway injury with vascular leak and airway cast formation as supported by our prior in vivo exposures 9,11,16,60 .…”

Section: Discussionmentioning

confidence: 86%

Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure

McGraw

Kim

White

et al. 2020

Annals of the New York Academy of Sciences

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Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 µM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 µM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 µM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 µM NM−exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustardinduced airway pathology.

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Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats

Cited by 30 publications

References 46 publications

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis

Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure

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